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Inhibition of caspase-1 activation in Gram-negative sepsis and experimental endotoxemia.

Abstract：

INTRODUCTION:Down-regulation of ex-vivo cytokine production is a specific feature in patients with sepsis. Cytokine downregulation was studied focusing on caspase-1 activation and conversion of pro-interleukin-1β into interleukin-1β (IL-1β). METHODS:Peripheral blood mononuclear cells were isolated from a) 92 patients with sepsis mainly of Gram-negative etiology; b) 34 healthy volunteers; and c) 5 healthy individuals enrolled in an experimental endotoxemia study. Cytokine stimulation was assessed in vitro after stimulation with a variety of microbial stimuli. RESULTS:Inhibition of IL-1β in sepsis was more profound than tumour necrosis factor (TNF). Down-regulation of IL-1β response could not be entirely explained by the moderate inhibition of transcription. We investigated inflammasome activation and found that in patients with sepsis, both pro-caspase-1 and activated caspase-1 were markedly decreased. Blocking caspase-1 inhibited the release of IL-1β in healthy volunteers, an effect that was lost in septic patients. Finally, urate crystals, which specifically induce the NLPR3 inflammasome activation, induced significant IL-1β production in healthy controls but not in patients with sepsis. These findings were complemented by inhibition of caspase-1 autocleavage as early as two hours after lipopolysaccharide exposure in volunteers. CONCLUSIONS:These data demonstrate that the inhibition of caspase-1 and defective IL-1 β production is an important immunological feature in sepsis.

journal_name

Crit Care

journal_title

Critical care (London, England)

authors

Giamarellos-Bourboulis EJ,van de Veerdonk FL,Mouktaroudi M,Raftogiannis M,Antonopoulou A,Joosten LA,Pickkers P,Savva A,Georgitsi M,van der Meer JW,Netea MG

doi

10.1186/cc9974

subject

Has Abstract

pub_date

2011-01-01 00:00:00

pages

R27

issue

1

eissn

1364-8535

issn

1466-609X

pii

cc9974

journal_volume

15

pub_type

杂志文章

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